EP0034546B1 - Nouveaux dérivés du cycloheptindole et leurs sels d'addition avec les acides, leur préparation, leur application comme médicaments et les compositions les renfermant - Google Patents

Nouveaux dérivés du cycloheptindole et leurs sels d'addition avec les acides, leur préparation, leur application comme médicaments et les compositions les renfermant Download PDF

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Publication number
EP0034546B1
EP0034546B1 EP81400272A EP81400272A EP0034546B1 EP 0034546 B1 EP0034546 B1 EP 0034546B1 EP 81400272 A EP81400272 A EP 81400272A EP 81400272 A EP81400272 A EP 81400272A EP 0034546 B1 EP0034546 B1 EP 0034546B1
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EP
European Patent Office
Prior art keywords
formula
product
carbon atoms
hydrogen atom
already indicated
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Expired
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EP81400272A
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German (de)
English (en)
French (fr)
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EP0034546A1 (fr
Inventor
Lucien Nedelec
Daniel Frechet
Claude Dumont
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Sanofi Aventis France
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Roussel Uclaf SA
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Priority to AT81400272T priority Critical patent/ATE7498T1/de
Publication of EP0034546A1 publication Critical patent/EP0034546A1/fr
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Publication of EP0034546B1 publication Critical patent/EP0034546B1/fr
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/94—[b, c]- or [b, d]-condensed containing carbocyclic rings other than six-membered
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to new cycloheptindole derivatives as well as their salts, their preparation process, the application as medicaments of these new derivatives and the compositions containing them.
  • the subject of the invention is the new derivatives of cycloheptindole, as well as their addition salts with mineral or organic acids, characterized in that they correspond to the general formula I: in which R represents a hydrogen atom, an alkyl radical containing from 1 to 5 carbon atoms, or an aralkyl radical containing from 7 to 12 carbon atoms optionally substituted by chloro, bromo, methyl, ethyl, methoxy, trifluoromethyl radicals or methylthio, R i represents a hydrogen, chlorine or bromine atom, and R 2 represents a hydrogen atom, an alkyl radical containing from 1 to 5 carbon atoms, cycloalkylalkyl containing from 4 to 7 carbon atoms, alkenyl or alkynyl containing 3 to 7 carbon atoms, or aralkyl containing 7 to 12 carbon atoms, optionally substituted by chloro, bromo, methyl, ethyl, methoxy, trifluoro
  • alkyl radical containing from 1 to 5 carbon atoms denotes, for example, a methyl, ethyl, propyl, isopropyl, butyl, isobutyl or pentyl radical;
  • aralkyl radical containing from 7 to 12 carbon atoms denotes, for example, a benzyl or phenethyl radical;
  • cycloalkylalkyl radical containing from 4 to 7 carbon atoms denotes, for example, a cyclopropylmethyl radical;
  • alkenyl radical containing 3 to 7 carbon atoms denotes, for example, an allyl or buten-2-yl radical;
  • alkynyl radical containing from 3 to 7 carbon atoms denotes, for example, a propargyl radical.
  • the addition salts with mineral or organic acids can be, for example, the salts formed with hydrochloric, hydrobromic, nitric, sulfuric, phosphoric, acetic, formic, propionic, benzoic, maleic, fumaric, succinic, tartaric, citric acids. , oxalic, glyoxyl, aspartic, alkane sulfonic such as methane or ethane sulfonic, arylsulfonic, such as benzene or paratoluene sulfonic and arylcarboxylic acids.
  • the dotted link means that the junction between the morpholino ring and the cycloheptene ring is trans.
  • R represents a hydrogen atom, a methyl radical or a benzyl radical
  • R 1 is as defined above
  • R 2 represents a hydrogen atom or an alkyl radical containing from 1 to 5 carbon atoms or cycloalkylalkyl containing from 4 to 7 atoms of carbon.
  • R represents a hydrogen atom
  • R 1 represents a hydrogen or bromine atom
  • R 2 represents a hydrogen or an alkyl radical containing from 1 to 5 carbon atoms, as well as their addition salts with mineral or organic acids, and very particularly the derivatives in the examples.
  • the condensation of the product of formula II with chloro acetyl chloride is advantageously carried out in the presence of an acid-fixing agent, preferably sodium hydroxide, in an organic solvent such as dioxane or tetrahydrofuran, but preferably the latter, in the presence of water.
  • an acid-fixing agent preferably sodium hydroxide
  • organic solvent such as dioxane or tetrahydrofuran, but preferably the latter, in the presence of water.
  • the cyclization of the product of formula III is preferably carried out using sodium hydride, but other bases such as sodium hydroxide or potash can be used; it is advantageously carried out in dimethylformamide or dimethoxyethane.
  • the reduction of the product of formula IV is preferably carried out using aluminum-lithium hydride.
  • a solvent such as dioxane, and preferably tetrahydrofuran.
  • the halogenating agent can be, for example, N-chloro succinimide, in the case of chlorination, N-bromo succinmmide, or preferably the brominated complex of 2-pyrrolidone of formula: in the case of bromination.
  • the halide of formula V is preferably an iodide; it reacts advantageously with the secondary amine of formula I A in the presence of an acid-fixing agent, such as, for example, an alkali carbonate such as potassium carbonate, in a solvent such as dimethylformamide.
  • an acid-fixing agent such as, for example, an alkali carbonate such as potassium carbonate
  • Formylation can be carried out using formic acid, but formylacetic anhydride is preferably used; the latter reagent is advantageously used in a solvent such as tetrahydrofu ranne.
  • the halide of formula Hal-R ' is preferably an iodide and the operation is carried out in a strongly basic medium, for example in the presence of sodium amide.
  • racemates of formula 1 can be resolved into their optically active enantiomers by methods known per se, such as, for example, the formation of salts by means of optically active acids.
  • the derivatives of formula 1 have a basic character.
  • the addition salts of the derivatives of formula 1 can advantageously be prepared by reacting, in substantially stoichiometric proportions, a mineral or organic acid with the said derivatives of formula I.
  • the salts can be prepared without isolating the corresponding bases.
  • the derivatives which are the subject of the present invention have very advantageous pharmacological properties; they are endowed in particular with remarkable dopaminergic and anti-anoxic agonist properties.
  • certain derivatives of formula 1 have, in addition, anti-ulcer properties.
  • the present application thus also relates to the application, as medicaments, of cycloheptindole derivatives, as defined by formula I, as well as of their addition salts with pharmaceutically acceptable acids.
  • the drugs which are the subject of the invention it is preferred to select the drugs characterized in that they consist of the new cycloheptindole derivatives corresponding to formula I, in which R represents a hydrogen atom or a radical benzyl, R 1 is as defined above and R 2 represents a hydrogen atom or an alkyl radical containing from 1 to 5 carbon atoms or cycloalkylalkyl containing from 4 to 7 carbon atoms, as well as by their addition salts with pharmaceutically acceptable acids.
  • R represents a hydrogen atom or a radical benzyl
  • R 1 is as defined above
  • R 2 represents a hydrogen atom or an alkyl radical containing from 1 to 5 carbon atoms or cycloalkylalkyl containing from 4 to 7 carbon atoms
  • R represents a hydrogen atom
  • R i represents a hydrogen or bromine atom
  • R 2 represents a hydrogen atom or an alkyl radical. containing from 1 to 5 carbon atoms, as well as their addition salts with pharmaceutically acceptable acids.
  • the medicaments according to the invention find their use, for example, in the treatment of neurological syndromes of extrapyramidal origin, for example in the treatment of Parkinson's disease and in the treatment of post-encephalitic parkinsonian syndromes; they can also be used in the treatment of hypersecretion of prolactin by the anterior pituitary gland, for example in the treatment of hypogonadism in women or men. They can also be used in the treatment of cerebral senescence or manifestations of cerebral hypoxia.
  • Certain medicaments according to the invention can also be used in particular for the treatment of hyperchlorhydria, gastric ulcers and gastroduodenal affections accompanied by gastric hyperacidity.
  • the usual dose which varies depending on the product used, the subject treated and the condition in question, for example, from 5 mg to 100 mg per day orally in humans with the derivative of Example 3 for the treatment of Parkinson's disease.
  • the invention finally relates to pharmaceutical compositions which contain at least one aforementioned derivative or one of its addition salts with pharmaceutically acceptable acids, as active principle.
  • the derivatives corresponding to formula 1 and their addition salts with pharmaceutically acceptable acids be incorporated into pharmaceutical compositions intended for the digestive or parenteral route.
  • compositions may be, for example, solid or liquid and be in the pharmaceutical forms commonly used in human medicine, such as, for example, tablets, simple or coated, capsules, granules, suppositories, injectable preparations; they are prepared according to the usual methods.
  • the active ingredient (s) can be incorporated therein into excipients usually used in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous vehicles or not , fatty substances of animal or vegetable origin, paraffinic derivatives, glycols, various wetting agents, dispersants or emulsifiers, preservatives.
  • the derivatives of formula II are new products.
  • the derivatives of formula II in which R2 "represents an alkyl radical containing from 1 to 5 carbon atoms, cycloalkylalkyl containing from 4 to 7 carbon atoms, or aralkyl containing from 7 to 12 carbon atoms which may be substituted can be prepared so general by reacting a product of formula II in which R 2 "represents a hydrogen atom, with trifluoroa anhydride ketic, preferably in the presence of a base, to obtain a product of formula VII: in which R has the meaning already indicated, which is reacted in the presence of a basic agent such as a carbonate or an alkali hydroxide, or a tertiary amine, with a halide of formula VIII: in which Hal and R 2 "have the meaning already indicated, to obtain a product of formula IX: in which R and R2 "have the meaning already indicated, which is subjected to an agent capable of hydrolyzing the
  • the product of formula II in which R and R 2 "represent a hydrogen atom can be prepared by treating the 3,4-dihydro 1H-cyclohept [c, d] indol-6-one described in Chem. Pharm. Bull. 25 (11), p. 3023, 1977, with tert-butyl nitrite in the presence of hydrochloric acid, then by reducing the keto-oxime obtained, for example by catalytic hydrogenation, followed by the action of sodium borohydride.
  • An example of such a preparation is given below in the experimental part.
  • Bosco et al described in Synthesis 2, 124 (1976), for example in the presence of a salt d quaternary ammonium, such as tetrabutyl ammonium chloride, benzyltriphenylphosphonium chloride, or preferably tetrabutyl ammonium hydrogen sulfate, aqueous sodium hydroxide and benzene, then preparation of the oxime and reduction as indicated above.
  • a salt d quaternary ammonium such as tetrabutyl ammonium chloride, benzyltriphenylphosphonium chloride, or preferably tetrabutyl ammonium hydrogen sulfate, aqueous sodium hydroxide and benzene
  • the base obtained above is dissolved in 80 cm 3 of methanol at 60 ° C, an excess of a hydrochloric acid solution in ethyl acetate is added, the mixture is cooled, drained and washed with ethyl acetate , dried, recrystallized from methanol and obtained 6.1 g of the desired pure product, in the form of a beige solid melting at more than 280 ° C with decomposition.
  • the acetate is a white crystallized solid melting at 165 ° C.
  • the 4.2 g of base are dissolved at 60 ° C. in 80 cm 3 of ethyl acetate, an excess of a solution of hydrochloric acid in ethyl acetate is added, concentrated under an inert atmosphere at room temperature , ice for 1 hour, drain, wash with ethyl acetate, dry, recrystallize from methanol and obtain 3.8 g of a white solid, melting at around 270 ° C.
  • Example 1 5.34 g of the product of Example 1 are suspended under an inert atmosphere at 60 ° C. for 4 hours, 8.46 g of potassium carbonate and 4.03 cm 3 of 98% iodopropane in 50 cm 3 of dimethylformamide, brings back to room temperature, adds 300 cm 3 of water, extracted with ethyl acetate, washes with water, dries, brings to dryness and obtains 5.5 g of the base of the sought product, melting at 170 ° C.
  • the base is dissolved in 120 cm 3 of ethyl acetate at 50 ° C, 60 ° C, slowly added with stirring 40 cm 3 of a solution of hydrochloric acid in ethyl acetate about 2N, crystallized under stirring at 50 ° C, left for 1 hour in the refrigerator, wrung, washed with ethyl acetate, dried at 60 ° C under reduced pressure, treated with activated carbon, recrystallized from methanol and obtained 4.35 g of a white solid melting at 260 ° C with decomposition.
  • 35 cm 3 of ammonia are condensed and 161 mg of sodium are added. Agitation is carried out for 15 minutes at -40 ° C., 20 mg of ferric nitrate is added, agitation is carried out for 20 minutes at -40 ° C., then 1.2 g of product obtained in Example 3 is rapidly added, in the form of the base solution in 18 cm 3 of tetrahydrofuran. Stirred for 10 minutes at -40 ° C, then added 0.5 cm 3 of methyl iodide. The temperature is allowed to rise, 150 cm 3 of water are added, extracted with methylene chloride, washed with a saturated aqueous solution of sodium chloride, dried, the solvent evaporated and 1.3 g of crude product are obtained. which is dissolved in ether. Treated with activated carbon, the solvent is evaporated and 1.25 g of expected product is obtained.
  • the mixture is refluxed for 2 hours, cooled, added in 30 minutes 50 cm 3 of tetrahydrofuran hydrated at 10%, diluted with 50 cm 3 of water, filtered, rinsed the filter with ethyl acetate, added chloride sodium in the filtrate, decanted, extracted with ethyl acetate, washed with water then using a saturated aqueous solution of sodium chloride, dried over sodium sulfate, distilled to dryness, and recovered 2 g of gross product.
  • the crystals are redissolved in 6 cm 3 of hot ethyl acetate, allowed to cool, initiates crystallization at ⁇ 15 ° ⁇ 20 ° C, left at this temperature for 1 hour 30 minutes, wrung, dried under reduced pressure at temperature ambient and obtains 4.03 g of white crystals melting at 100 ° C.
  • the lesion is carried out in male rats of approximately 220 g by unilateral injection into the nigrostriated dopaminergic bundle, of 8 ⁇ g of 6-hydroxydopamine in solution at 2 ⁇ g / ⁇ l (U. Ungerstedt, Acta Physiol. Scand. 1971, 82, suppl 367, 69 ⁇ 93).
  • direct dopaminergic agonists such as apomorphine
  • apomorphine administered generally, cause rotational behavior in the contralateral direction to the injured side.
  • test compound is administered at least 5 weeks after the injury.
  • the animals are placed in an automated rotometer which makes it possible to count the number of rotations carried out by each animal in both directions.
  • Example 1 The products of Examples 1, 2 and 3 were administered by the intraperitoneal route.
  • the product of Example 1 caused 337 ⁇ 99 contralateral rotations at the dose of 5 mg / kg
  • the product of Example 2 364 ⁇ 50 contralateral rotations at the dose of 1 mg / kg
  • the product of 1 'example 3 657 ⁇ 205 contralateral rotations at a dose of 0.1 mg / kg.
  • the curve for the binding percentage of spiroperidol 3 H is established as a function of the concentration of the product to be tested.
  • inhibitory concentration 50 The concentration of the product to be tested, which inhibits by 50% the maximum binding of spiroperidol 3 H, is called inhibitory concentration 50.
  • mice Male mice weighing 20 to 22 g, fasted for 5 hours, divided into groups of 10 animals, are used. The survival time of the mice placed in an airtight enclosure in which the pressure is brought to 90 mm of mercury is determined by means of a pump. The products studied are administered orally, thirty minutes before the test. Cookies do not receive any product. The observation is carried out for 2 minutes.
  • the SHAY technique consists in inducing ulcers in the stomach in rats, by ligating the pylorus.
  • the animals are anesthetized with ether.
  • a longitudinal incision is made about 1 cm below the sternum, the glandular part of the stomach and the duodenum are exposed, and a ligature is placed a few mm below the pylorus.
  • the muscular plan is left as it is and the skin is sutured by 2 staples.
  • the animals receive immediately afterwards the dispersant or the substance to be studied, by the oral route, in a volume of 0.5 ml / 100 g, and are kept without food or drink until sacrifice by carotid bleeding which takes place approximately 16 hours. after treatment.
  • a ligature is placed above the cardia.
  • Gastric fluid is collected to measure its pH.
  • the stomach is then opened according to the great curvature, rinsed in physiological saline, and spread on millimeter paper to be examined under a binocular magnifying glass.
  • the severity of the lesions is evaluated macroscopically, which is scored from 0 to 4 for each stomach.
  • the average intensity of the ulcers is determined for each batch of rats and the protection is calculated by relating the average index of the group to the average index of the control group.
  • the lethal dose DL o of the derivatives of Examples 1 and 3 tested after oral administration in mice was evaluated.
  • the maximum dose which causes no mortality is called DL o .

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Indole Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
EP81400272A 1980-02-26 1981-02-20 Nouveaux dérivés du cycloheptindole et leurs sels d'addition avec les acides, leur préparation, leur application comme médicaments et les compositions les renfermant Expired EP0034546B1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AT81400272T ATE7498T1 (de) 1980-02-26 1981-02-20 Cycloheptindolderivate und ihre saeureadditionssalze, ihre herstellung, ihre verwendung als arzneimittel und sie enthaltende zusammensetzungen.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR8004198 1980-02-26
FR8004198A FR2476649A1 (fr) 1980-02-26 1980-02-26 Nouveaux derives du cycloheptindole, leurs sels, procede de preparation, application a titre de medicaments et compositions les renfermant

Publications (2)

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EP0034546A1 EP0034546A1 (fr) 1981-08-26
EP0034546B1 true EP0034546B1 (fr) 1984-05-16

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EP81400272A Expired EP0034546B1 (fr) 1980-02-26 1981-02-20 Nouveaux dérivés du cycloheptindole et leurs sels d'addition avec les acides, leur préparation, leur application comme médicaments et les compositions les renfermant

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US (1) US4313944A (enrdf_load_stackoverflow)
EP (1) EP0034546B1 (enrdf_load_stackoverflow)
JP (2) JPS56133266A (enrdf_load_stackoverflow)
AT (1) ATE7498T1 (enrdf_load_stackoverflow)
CA (1) CA1161038A (enrdf_load_stackoverflow)
DE (1) DE3163567D1 (enrdf_load_stackoverflow)
FR (1) FR2476649A1 (enrdf_load_stackoverflow)
ZA (1) ZA811149B (enrdf_load_stackoverflow)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2479830A1 (fr) * 1980-04-03 1981-10-09 Roussel Uclaf Nouveaux derives de l'indolobenzoxazine, leurs sels, procede de preparation, application a titre de medicaments et compositions les renfermant
US4349548A (en) * 1981-11-20 1982-09-14 Merck & Co., Inc. Octahydrobenzo[6,7]cyclohept[1,2-b]-1,4-oxazines, compositions and use
FR2533215A1 (fr) * 1982-09-20 1984-03-23 Roussel Uclaf Nouveaux derives de la c-homo 9-oxaergoline, leurs sels, procede de preparation et intermediaires de preparation, application a titre de medicaments et compositions les renfermant
FR2594828B1 (fr) * 1986-02-24 1988-07-01 Roussel Uclaf Derives du tetrahydrobenz (c,d) indole, leurs sels, procede de preparation, application a titre de medicaments, compositions les renfermant et intermediaires

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4238486A (en) * 1979-11-23 1980-12-09 Merck & Co., Inc. Indolobenzoxazines

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Néant *

Also Published As

Publication number Publication date
ATE7498T1 (de) 1984-06-15
ZA811149B (en) 1982-03-31
CA1161038A (fr) 1984-01-24
DE3163567D1 (en) 1984-06-20
FR2476649B1 (enrdf_load_stackoverflow) 1982-03-05
JPS56133266A (en) 1981-10-19
JPH0148268B2 (enrdf_load_stackoverflow) 1989-10-18
FR2476649A1 (fr) 1981-08-28
EP0034546A1 (fr) 1981-08-26
US4313944A (en) 1982-02-02
JPS56133292A (en) 1981-10-19

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